Microbiologically active quaternary ammonium compounds



MICROBIOLOGICALLY ACTIVE QUATERNARY AMMONIUM COMPOUNDS taste a31 5i? t Emimw l are 3 t 361 @795? (7 r; m... V? et". MI. W

nlted Stan a WW v H Jan. 2, 1968 alysis of the Association of Ofiicial Agricultural Chem- 3,361,795 ists, ninth edition (1960), page 63 at seq.

The 4.4-bis(p-hydroxyphenyl) pentanoic acid which is used in this invention is commercially available under the gi i g g l and Josepll 5 designation of Di-Phenolic Acid from S. C. Johnson gg f is i gg 'g a ?ggg g t gs $55: 2nd Son, Incorporated in Racine, Wis. and is described a corporation of New York y them as produced by the condensatlon of phenol and No Drawing. Filed Apt 13, 1964 Sen 359,501 levultnic acld. Di-Phenolic Acld, as well as DPA- 13 (jl i ,(C 2 0 501 15 hereinafter used, are registered trademarks of S. C.

10 Johnson and Son, Incorporated. Derivatives such as 4,4-

The present invention has for its object the preparation bis(nitro-hydroxyphenyl) pentanoic acid can be obtained of relatively insoluble, microbiologically active comsimilarly by the condensation of nitrophenol with levupounds by reaction of certain quaternary ammonium hylinic acid and analogous compounds may also be predroxides or their water-soluble salts with 4,4-bis(p-hypared by substituting for nitrophenol, for example, haldroxyphenyl)pentanoic acid and certain of its derivatives 1 ophenols and the like. Derivatives of 4,4bis(p-hydroxyor their water-soluble salts. phenyl) pentanoic acid may also be obtained by reacting The quaternary ammonium compounds used in the the phenolic hydroxy groups of that compound with process of this invention contain at least one carbon chain such agents as carboxylic acids to yield phenolic ester having from 8 to 22 carbon atoms and also possess at groups or with alkyl halides to yield phenolic ether least one benzyl radical attached to the quaternary nitrogroups. Other derivatives may also be obtained by reactgen atom. The benzyl radical may, if desired, be substituted by alkyl groups or halogen atoms. The quaternary ammonium compounds, moreover, possess only nonheterocyclic nitrogen atoms. In general, the quaternary ammonium compounds used in the present invention comply with the formula:

ing the activated hydrogens in the 3 and 5 positions of one or both of the phenyl nuclei by halogenation, nitration, sulfonation and alkylation. Other derivatives may also be obtained by means of the Mannich reaction, wherein formaldehyde and ammonia or alkyl amines are employed to attach one or more amino groups in the 3 and 5 positions of one or both of the phenyl nuclei.

Other derivatives may also be made by condensing two N or more molecules of the 4,4-bis(p-hydroxyphenyl) pentanoic acid by reacting them with a suitable proportion where R is an alkyl radical containing from 8 to 22 carbon atoms or an alkyl benzyl radical in which the benzyl group may contain a substituent methyl radical and in which the alkyl group contains 8 to 22 carbon atoms and R" is a benzyl or substituted benzyl radical or a methyl group if R is an alkyl benzyl radical containing eight or more carbon atoms in its alkyl substituent. X in the above formula is chlorine, bromine, iodine, sulfate, methosulfate, ethosulfate and the like.

Typical examples of these quaternary ammonium compounds are alkyl dimethyl benzyl ammonium chloride in which the alkyl group may have from 8 to 22 carbon atoms, alkyl dimethyl substituted benzyl ammonium chlorides in which the alkyl radical contains from 8 to 22 w carbon atoms and in which the benzyl radical is substituted with one or more side chains containing from 1 to 5 carbon atoms such, for example, as methyl, dimethyl, trimethyl, tetramethyl, ethyl, diethyl, isopropyl, tertiary of a dihaloalkane such as dichlorobutane or with dichloroethyl ether or with epichlorohydrin and the like to form polyether acids.

Ty ical of the derivatives of the 4,4-bis(p-hydroxyphenyl) pentanoic acid which may be used in this invention, in addition to the acid itself, are the monoand dichloro, monoand dibromo, monoand dinitro, monoand dimethyl, monoand disulfonic acid, monoand di-methyl-, ethyl-, propylor butylether, monoand diformic, acetic or propionic ester, monoor polyamino-, methyl aminoor dimethyl aminophenyl substituted compounds and the like. .Also, we may use poly ether acids containing on the average from two to five acid units joined with either bridges.

The quaternary ammonium salts of 4,4-bis(p-hydroxyphenyl) pentanoic acid, otherwise called Di-Phenolic Acid, or for the sake of brevity DPA, and its derivatives embraced within the scope of this invention may be repbutyl and isoamyl or with one, two or more halogen atoms resented as follows:

OH; on, Y o- 3-o[-R-o--d o -z zlz (dust JOOX (ilOOXt such as chlorine and bromine, alkyl dimethyl menaphthyl ammonium chloride and alkyl dimethyl tetrahydromenaphthyl ammonium chloride in which the alkyl radical contains from 8 to 22 carbon atoms, alkyl benzyl trimethyl ammonium chloride in which the alkyl radical contains from 8 to 22 carbon atoms and in which the aromatic nucleus of the benzyl radical may, if desired, be substituted by one or more methyl or other lower alkyl groups and mixtures of the aforesaid quaternary ammonium compounds.

In general, we prefer to use such quaternary ammonium compounds which have a phenol coefficient of at least 100 with respect to both Staphylococcus aureus and Salmonella typhosa at 20. C. when determined by the standard method given in the Oflicial Methods of Anwherein R may be (CH or or CH -CHOH-CH and the like, and n is any number from zero to four on the average, and X X Y and Z may be hydrogen, a metal, an organic base and at least one of which is a quaternary ammonium cation, and one ore more of the 3 or 3,5 positions of one or more of the benzene rings may be nitro, halo, alkyl or sulfonic acid substituted.

The compounds of this invention may be prepared by mixing aqueous solutions of the quaternary ammonium salts or hydroxides with an aqueous solution of the acid in question or any of its water-soluble salts. The ratio of quaternary ammonium compound to acid should be such as to permit complete salt formation between the quaternary ammonium compound and all of the carboxylic groups, or the carboxylic and one or both of the phenolic groups if any, of the 4,4-bis(p-hydroxyphenyl) pentanoic acid or its derivatives. Thus, mono, di or tri quaternary ammonium salts may be formed.

In the case of the polyether acids, the carboxylic salts are normally considered, but the salts of the residual phenolic groups may also be included, if desired.

After thorough mixing, the organic product layer is separated from the aqueous layer (as with a separator-y funnel) since two distinct phases are formed. Separation may be facilitated by the addition of an organic solvent immiscible with water. The product layer may be washed with water to remove any residual by-product salt or unreacted materials. The solvent, if any, may be evaporated and the product air or vacuum dried to a paste, wax, oil or solid.

It is not necessary to use an aqueous medium. Any solvent or solvent mixture in which the starting materials are soluble will be satisfactory. Non-aqueous solvents facilitate the separation of by-product inorganic salt and reduce the need for vacuum drying to get an anhydrous product. When a non-aqueous medium is employed, it is usually necessary to add a small amount of water to facilitate ionic reaction.

The product may be used, if desired, without drying since any entrapped water is irrelevant to the microbiological activity of the compounds. In other applications, removal of water may be essential for reasons not related to biological activity.

An alternative method for the preparation of compounds especially applicable to the treatment of fabric,

' ropes, net woven and non-woven fabric and reticulated or convoluted materials, involves a two-step process. In the first step, the material is passed through a bath containing the anionic moiety. Excess solution is removed by methods well known to those skilled in the art. The treated material is then passed through a second bath wherein the concentration of quaternary ammonium compound is such that the material pickup will result in an equivalent amount of quaternary ammonium compound reacting with the anionic moiety, depositing the product in the most intimate way on the surface and in the interstices, convolutions and reticulations of the material.

The method of adjustment of solution concentration to achieve the required pickup is well known to those skilled in the art. The order of treatment may be reversed without affecting the biological activity or durability of the product on the material. The products of this invention may be formulated as water dispersions by dissolving them in a water-miscible organic solvent such as acetone or methanol and diluting with water or by dissolving them in emulsifiable oils such, for example, as sulfonated castor oil or pine oil and diluting water water. In preparing aqueous dispersions, emulsifying agents such, for example, as ethylene oxide condensates of alkyl phenols may be used with or without organic solvents.

It is surprising that the compounds of this invention exhibit high microbiological activity despite their relative insolubility in water. Because of their unusual combination of physical and microbiological properties, they can be used to impart laundry-resistant anti-microbial characteristics to textiles. They can also be used as the active agent in antimildew finishes for textiles which are resistant to leaching with water.

Although the compounds have low water solubility, they are compatible with various organic solvents, plasticizers and high molecular weight compounds. Consequently, they may be incorporated as anti-microbial agents in synthetic resins and plastics. The compounds are compatible with natural and synthetic rubber latices. Therefore, they may be used to prepare bacteriostatic films and molded objects deposited from such latices.

The compounds can be incorporated into cutting and grinding fluids without precipitation. Also, they blend well with non-ionic and anionic surface active agents. lnv such compositions they retain their microbiological activity.

It will be understood that the properties of the products described herein willv vary depending upon the nature of the quaternary ammonium compound used in their preparation as well as the aromatic carboxylic acid or salt reacted therewith.

The chemical, physical and biological properties of the products of our invention make them especially appropriate for the following applications when suitably incorporated in active amounts in an appropriate vehicle. binder, medium or substrate:

(l) Mildewproofing fabric, canvas, ropes, textiles, awnings, sails, tenting and other woven and nonwoven reticulated materials.

(2) Paint mildewstats.

(3) Jet plane fuel additive to control growth of microorganisms.

(4) Odor preservative agents for clothes and shoes.

(5) Mildew retardant and odor suppressant for shoes and other leather products.

(6) Topical antiseptics.

(7) Antidandruif agents.

(8) Disinfection agents for hair and gut of man and beast.

(9) Bacteriostatic furniture dressing.

(10) Surface finishes for stone, plaster, tile, cement, brick and other inorganic building materials, to retard growth of microorganisms, fungi, mold and algae.

(ll) Wool preservative.

(12) Plant and tree spray to combat fungi.

(l3) Antimycotic agents for soap wrappers.

(l4) Self-sanitizing brushes.

(l5) Mildewproofing agent in and on plastic and film.

(16) Mildewproofing of cellulosics, cardboard, fibre board, paper and cordage.

(17) Contact biostat for application to film, waxes and cloth to preserve cheese, meats and vegetables and other food products.

(18) Algal inhibition, especially on surfaces and in solution where low foaming is desirable.

(19) Paper pulp slime control.

(20) Sanitizing agent for rug, carpet, curtains.

(21) Egg preservation.

(22) Adhesive preservation.

(23) Preservation of latex paints.

(24) Preservation of metal-working compounds.

(25) Additives for soap and for both anionic and non ionic detergents in liquid, bar, powder, bead, solution and other forms to impart bacteriostatic and fungistatic properties thereto.

The microbiological activity of our compounds has been evaluated for microbiological stasis by the Standard. Tube Dilution Test, the technique for which is common knowledge to those skilled in the art. A Difco Bacto CSMA Broth #0826 was used in the study. This test is used to determine the lowest concentration of microbiologically active compounds which will inhibit the growth of the organism in question. For a wide range of applications, the inhibition of growth rather than outright kill is satisfactory.

Briefly put, the Tube Dilution Test consists in placing 9 cc. of the CSMA Broth in a test tube which is then sterilized in an autoclave. One cc. solution of the micro-- biologically active compound at an appropriate concentration is added to the test tube which is then inoculated with (H cc. of a twenty-four hour old culture of the organism under study. The test tube is then incubated at 37 C. for forty-eight hours and observed for bacterial growth.

The same procedure is followed for fungi. In such tests, however, the tubes are incubated for fourteen days at a temperature suitable for optimum fungal growth, usually 25 C.

The invention is illustrated by, but not restricted to, the following examples:

EXAMPLE I A stock solution was prepared in concentration of the monosodium salt of 4,4-bis(p-hydroxyphenyl) pentanoic acid. Sixty ml. of this solution containing 0.0195 chemical equivalent weights of the compound was agitated vigorously while adding 80 ml. of an 11% solution of a commercial grade of alkyl dimethyl ethyl-benzyl ammonium chloride (Onyx Chemical Corporations ETC-471 in which the alkyl distribution is 50% C 30% C 17% C 3% C The agitated mixture was transferred to a separatory funnel where two phases separated. The organic product layer was removed and vacuum dried to yield a brown paste in 90% of theoretical yield of alkyl dimethyl ethyl-benzyl ammonium bis (phydroxyphenyl) pentanoate.

EXAMPLE II The stock solution of monosodium salt of 4,4-bis(phydroxyphenyl) pentanoic acid of Example I was reacted in the same manner with a chemically equivalent amount of a solution of a commercial grade of alkyl dimethyl benzyl ammonium chloride (Onyx Chemical Corporations BTC824 in which the alkyl distribution is 60% C 30% C 5% C 5% C The vacuum dried product was a brown paste in 100% of the theoretical yield of alkyl dimethyl benzyl ammonium bis(p-hydroxyphenyl) pentanoate.

EXAMPLE III A 10% stock solution of the disodium salt of 4,4-bis (phydroxyphenyl) pentanoate was prepared. An aliquot of this solution containing 0.0182 molecular weights was agitated vigorously and two chemically equivalent weights of the solution of the alkyl dimethyl ethyl-benzyl ammonium chloride of Example I was added. On separating and vacuum drying the organic product layer, a brown paste was obtained in 50% of the theoretical yield of the di(a1kyl dimethyl ethyl-benzyl ammonium) salt of bis(phydroxyphenyl) pentanoic acid.

/ EXAMPLE IV In a similar manner, 60 ml. of the stock solution of the disodium salt of 4,4-bis(p-hydroxyphenyl) pentanoic acid of Example III was reacted with two chemically equivalent weights of the solution of the alkyl dimethyl benzyl ammonium chloride of Example II. The recovered and vcauum dried product was a brown paste in 62% of the theoretical yield of the di(alkyl dimethyl benzyl ammonium) salt of bis(p-hydroxyphenyl) pentanoic acid.

EXAMPLE V A solution was prepared in 10% concentration of the trisodium salt of 4,4-bis(p-hydroxyphenyl) pentanoic acid. An aliquot of this solution containing 0.0170 molecular weights was reacted with three chemically equivalent weights of a solution of the alkyl dimethyl ethyl-benzyl ammonium chloride of Example I while agitating vigorously. The mixture was transferred to a separatory funnel and allowed to separate into two phases. The organic product layer was removed and vacuum dried. The resulting brown paste was recovered in 44% of the theoretical yield of, tri(alky1 dimethyl ethyl-benzyl ammonium) salt of his (p-hydroxyphenyl) pentanoic acid.

EXAMPLE VI A solution of the monosodium salt of 4,4-bis(3-nitro-4- hydroxyphenyl) pentanoic acid was prepared in 5% concentration. An aliquot of this solution containing 0.00753 molecular weights of the compound was agitated vigorous- 1y while a chemically equivalent amount of the solution of alkyl dimethyl ethyl-benzyl ammonium chloride of Ex ample I was added. The mixture was transferred to a sep aratory funnel along with a small amount of benzene to facilitate phase separation. The organic product layer was removed and vacuum dried. A red paste was obtained in 98% of the theoretical yield of alkyl dimethyl ethyl-benzyl. ammonium bis(3-nitro-4-hydroxyphenyl) pentanoate.

EXAMPLE VII A polyether acid was prepared by reacting 4,4-bis(p hydroxyphenyl) pentanoic acid and dichloroethyl ether in such proportions that on the average there were approximately four carboxylic acid groups in the molecule. It was found to have an acid number of 156.7 and therefore a combining weight of 358.

A 10% stock solution of the sodium salt of this compound was prepared in water. An aliquot containing. 0.0158 chemical equivalents was agitated vigorously and a chemically equivalent amount of a solution of the alkyl dimethyl ethyl-benzyl ammonium chloride of Example I was added. The mixture was poured into a separatory funnel and allowed to separate into two phases. The organic product layer was vacuum dried to yield a brown paste in the theoretical yield of poly(alkyl dimethyl ethylbenzyl ammonium) salt of the said polyether acid.

In a similar manner, by using the alkyl dimethyl benzyl ammonium chloride and the technique of Example III, the poly(alkyl dimethyl :benzyl ammonium) salt of the polyether acid was obtained in theoretical yield.

EXAMPLE VIII A polyether acid was prepared by reacting 4,4-bis(p hydroxyphenyl) pentanoic acid and epichlorohydrin in such proportions that there were approximately four car boxylic acid groups in the molecule. It was found to have an acid number of 15S and therefore a combining weight of 362.

A 10% stock solution of the sodium salt of this compound was prepared in water. An aliquot of this solution containing 0.0339 chemical equivalents was agitated vigorously While adding a solution of the alkyl dimethyl ethylbenzyl ammonium chloride of Example I, in chemically equivalent amount. The mixture was separated into two phases in a separatory funnel and the organic product layer was removed and vacuum dried. A brown solid was obtained in 93% of the theoretical yield of the poly(alkyl dimethyl ethyl-benzyl ammonium) salt of the said poly-- ether acid.

In a similar manner, by substituting the alkyl dimethyl benzyl ammonium chloride of Example II for the alkyl dimethyl ethyl-benzyl ammonium chloride of Example I, the poly(alkyl dimethyl benzyl ammonium) salt of the said polyether acid was obtained in 100% of the theoretical yield.

EXAMPLE IX A polyether acid was prepared by reacting 4,4-bis(p" hydroxyphenyl) pentanoic acid with 1,4-dichloro butane in such proportions that on the average there were ap proximately five carboxylic acid groups in the molecule. It was found to have an acid number of 137 and therefore a combining weight of 410.

A 10% stock solution of the sodium salt of this compound was prepared. An aliquot of the solution containing 0.0231 chemical equivalents was agitated vigorously and a chemically equivalent amount of a solution of the alkyl dimethyl ethyl-benzyl ammonium chloride of Example I was added. The mixture was transferred to a separatory funnel, wherein two phases separated. The organic product layer was removed and vacuum dried. A brown solid product of poly(alkyl dimethyl ethyl-benzyl ammonium) salidof the said polyether acid was obtained in theoretical yie In a similar manner, using the alkyl dimethyl benzyl ammonium chloride of Example II, the poly(alkyl di- 7 methyl benzyl ammonium) salt of the said polyether acid. was obtained in 100% of theoretical yield as a brown solid.

EXAMPLE X The microbiological activity of the products of this invention is illustrated in Table I which shows the results obtained by means of the Standard Tube Dilution Test described above. The performance of the products listed in this table was determined with respect to Staphylococcus rmreus (S.a.), Salmonella typllosa (St) and Aspcrglllus niger (A.n.).

Table I 4,4-bis(p-hydroxyphenyl) pentanoic acid is designated. below as DPA for the sake of brevity. The polyether acid obtained by reacting four mols of DPA with three of dichloro ethyl ether is designated as 4 DPA-3 E; the polyether acid from four mols of DPA with three of epichlorohydrin as 4 DPA-3 G.

Reciprocal of Static Dilution of Product Quaternary Acid vs.-

5.11. S.t l A n Alkyl DimethyL DPA, Mono Salt ll) I 10 Etliyl-Benzyl 1) PA, Di Salt 10 10 10 Ammonium 10 10 10 Chloride 10 10" 10 DP 10 10 1O 10" 10 10 tlkyl Dimethyl 10 10 10 Benz 13' 10 10 Ammonium 10 10 10 Chloride 10 10' 10 4 DPA'3 G 10 10" 10 We claim:

1. A quaternary ammonium salt of 4.4-bis(p-hydroxyphenyl) pentanoic acid and its derivatives having the formula:

2. Alkyl dimethyl ethyl-benzyl ammonium 4,4-bis(phydroxy phenyl) pentanoate, wherein the alkyl has from 12 to 18 carbon atoms.

3. Alkyl dimethyl benzyl ammonium 4,4-bis(p-hydroxyphenyl) pentanoate, wherein the alkyl has from 12 to 18 carbon atoms.

4. Di(alkyl dimethyl ethyl-benzyl ammonium) 4,4-bis (p-hydroxyphenyl) pentanoate, wherein the alkyl has from 12 to 18 carbon atoms.

5. Di(alkyl dimethyl benzyl ammonium) 4,4-bis(phy droxyphenyl) pentanoate, wherein the alkyl has from 12 to 18 carbon atoms.

6. Tri(alkyl dimethyl ethyl-benzyl ammonium) 4,4-bis (p-hydroxyphenyl) pentanoate, wherein the alkyl has from 12 to 18 carbon atoms.

7. Alky] dimethyl ethyl-benzyl ammonium 4,4-bis(3- nitro-4-hydroxyphcnyl) pentanoate, wherein the alkyl has from 12 to 18 carbon atoms.

8. Poly(alkyl dimethyl ethyl-benzyl ammonium)salt of the polyether acid reaction product of 4,4-bis(p-hydroxyphenyl) pentanoic acid and dichloroethyl ether and having on the average about four carboxylic acid groups in the molecule, wherein the alkyl has from 12 to 18 carbon atoms.

9. Poly(alkyl dimethyl benzyl ammonium) salt of the polyether acid reaction product of 4,4-bis(p-hydroxy-- phenyl) pentanoic acid and dichloroethyl ether and hav ing on the average about four carboxylic acid groups in the molecule, wherein the alkyl has from 12 to 18 carbon atoms.

10. Poly(alkyl dimethyl ethyl-benzyl ammonium) salt of the polyether acid reaction product of 4,4-bis(p-hy droxyphenyl) pentanoic acid and epichlorhydrin and containing about four carboXylic acid groups in the molecule, wherein the alkyl has from 12 to 18 carbon atoms.

11. Poly(alkyl dimethyl benzyl ammonium) salt of the polyether acid reaction product of 4,4-bis(p-hydroxyphenyl) pentanoic acid and epichlorhydrin and containing about four carboxylic acid groups in the molecule, wherein the alkyl has from 12 to 18 carbon atoms.

wherein R is an alkyl of 8 to 22 carbon atoms, R" is a member of the group consisting of benzyl and substituted benzyl wherein the substituent is a member of the group consisting of alkyl having 1 to 5 carbon atoms, chlorine and bromine, said quaternary ammonium cation being at least one of said X, X Y and Z,

12. Poly(alkyl dimethyl ethyl-benzyl ammonium) salt of the polyether acid reaction product of 4,4-bis(p-hydroxyphenyl) pentanoic acid and 1,4-dichloro butane and having about five carboxylic acid groups in the molecule, wherein the alkyl has from 12 to 8 carbon atoms.

13. Poly(alkyl dimethyl benzyl ammonium) salt of the polyether. acid reaction product of 4,4-bis(p-hydroxyphenyl) pentanoic acid and 1,4-dichloro butane and having about five carboxylic acid grOups in the molecule, wherein the alkyl has from 12 to 18 carbon atoms,

References Cited UNITED STATES PATENTS 2,108,765 2/1938 Domagk 260-567 2,676,986 4/1954 Wakeman et al 260576 2,907,747 10/1959 Greenlee 260-520 2,933,520 4/1960 Bader 260520 3,133,944 5/1965 Christenson 260520 LORRAINE A. WEINBERGER, Primary Examiner. M. B. WEBSTER, Assistant Examiner. 

1. A QUATERNARY AMMONIUM SALT OF 4.4-BIS(P-HYDROXYPHENYL) PENTANOIC ACID AND ITS DERIVATIVES HAVING THE FORMULA: 